1. Field of the Invention
The invention relates to a process for the preparation of D-(-)-phenylglycine chloride hydrochloride by chlorinating D-(-)-phenylglycine hydrochloride, which as such is prepared in situ from D-(-)-phenylglycine and hydrochloric acid gas, in a solvent.
2. Brief Description of Related Art
D-(-)-phenylglycine chloride hydrochloride is a particularly valuable substance; after all, this substance is used in the preparation of antibiotics. D-(-)-phenylglycine chloride hydrochloride is an indispensable starting material in the preparation of the half-synthetic penicillins, such as ampicillin; the half-synthetic cephalosporin, cefalhexin; and bactericides such as tetrazolylpenams and spiropenams.
As is known, D-(-)-phenylglycine chloride hydrochloride is prepared by chlorinating D-(-)-phenylglycine hydrochloride with phosphorus pentachloride in a solvent which does not dissolve the starting product and the end product and whereby phosphorus oxychloride is obtained as a by-product. Separation by filtration yields a non-dividable mixture of D-(-)-phenylglycine chloride hydrochloride and the non-reacted starting substance. As D-(-)-phenylglycine chloride hydrochloride is used in the preparation of medicines, it must be of the highest possible purity. Nowadays it is a requirement that the content of D-(-)-phenylglycine chloride hydrochloride in the end-product is 96% or more.
In order to meet this requirement it is necessary in the known methods to carry out the chlorination in chlorinated solvents such as: dichloromethane, chloroform, dichloroethane, carbon tetrachloride or mixtures of such chlorinated solvents. It is generally known that this type of chlorinated solvents is very harmful. For humans they are toxic and some of them are even carcinogenic. For the environment they are very harmful because they are not biologically degradable. These adverse characteristics cause various problems when using the above-mentioned chlorinated solvents in the preparation of D-(-)-phenylglycine chloride hydrochloride. From a hygienic and safety point of view the treatment of the process solution is obstructed. The losses during the working up of the process solution have a destructive effect on the environment, and the volatility of these solvents aggravates the problem even more. There are also disadvantages with a view to the end-product, as there is always a small but not removable amount of solvent remaining in the dried D-(-)-phenylglycine chloride hydrochloride. As this product is used in the preparation of medicines it is not acceptable that it should contain toxic or carcinogenic substances. In addition it must be considered that legislation in western countries, and gradually also in the rest of the world, is focussed at a decrease and eventual discontinuation of the use of chlorinated solvents.
All the patents and technical literature known up to now describe the use of chlorinated solvents for the preparation of D-(-)-phenylglycine chloride hydrochloride. The French patent specification 1.332.557 (Jul. 19, 1963) Chem. Abstr. 60 P1761b! to Bristol-Meyers, Co., describes the preparation in both dichloromethane and carbon tetrachloride. In the article by G. A. Hardcastle et al (J. Org. Chem., 31 (1966), 897-899) the preparation of D-(-)-phenylglycine chloride hydrochloride is also carried out in dichloromethane. In 1973 Ajinomoto Co., Inc. patented the preparation of the same product in JP 73 13.301 (Feb. 20, 1973) Chem. Abstr. 78 P13-6660h! using dichloroethane as solvent. Chinoin in HU 183.548 (Aug. 29, 1983) Chem. Abstr. 100 P68733e! describes the process using dichloromethane or carbon tetrachloride as solvent. The latest known patent is from 1989, DD 264,689 (Feb. 8, 1989) Chem. Abstr. 111 P97719n!, in which VEB Berlin-Chemie patents the preparation of D-(-)-phenylglycine chloride hydrochloride in dichloromethane.
The use of non-chlorinated solvents in the preparation of D-(-)-phenylglycine chloride hydrochloride has not been possible up to now. Chlorination of D-(-)-phenylglycine hydrochloride carried out in a non-chlorinated solvent yields an end-product having such a low content of the desired compound, that it is not suitable for the manufacture of medicines. That means that the use of non-chlorinated solvents is excluded as one obtains D-(-)-phenylglycine chloride hydrochloride of poor quality, due to the starting substance being left behind in the end-product.
Moreover, it should be noted that the product obtained does not show a well defined crystalline structure, but that there are substantial differences in particle size and also, that these have, in part, an amorphous structure. This is disadvantageous when using this D-(-)-phenylglycine chloride hydrochloride in the preparation of medicines as these reactions are also carried out heterogeneously and the reaction rates of the different modifications and sizes vary.
The invention provides thus a process in which the above-mentioned disadvantages are alleviated.